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J Biol Chem. 2016 Jun 24;291(26):13649-61. doi: 10.1074/jbc.M116.719039. Epub 2016 Apr 28.

Formation of Functional Heterodimers by TREK-1 and TREK-2 Two-pore Domain Potassium Channel Subunits.

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From the Department of Physiology, Semmelweis University, H-1428 Budapest, Hungary.
From the Department of Physiology, Semmelweis University, H-1428 Budapest, Hungary


Two-pore domain (K2P) potassium channels are the major molecular correlates of the background (leak) K(+) current in a wide variety of cell types. They generally play a key role in setting the resting membrane potential and regulate the response of excitable cells to various stimuli. K2P channels usually function as homodimers, and only a few examples of heteromerization have been previously reported. Expression of the TREK (TWIK-related K(+) channel) subfamily members of K2P channels often overlaps in neurons and in other excitable cells. Here, we demonstrate that heterologous coexpression of TREK-1 and TREK-2 subunits results in the formation of functional heterodimers. Taking advantage of a tandem construct (in which the two different subunits were linked together to enforce heterodimerization), we characterized the biophysical and pharmacological properties of the TREK-1/TREK-2 current. The heteromer was inhibited by extracellular acidification and by spadin similarly to TREK-1, and its ruthenium red sensitivity was intermediate between TREK-1 and TREK-2 homodimers. The heterodimer has also been distinguished from the homodimers by its unique single channel conductance. Assembly of the two different subunits was confirmed by coimmunoprecipitation of epitope-tagged TREK-1 and TREK-2 subunits, coexpressed in Xenopus oocytes. Formation of TREK-1/TREK-2 channels was also demonstrated in native dorsal root ganglion neurons indicating that heterodimerization may provide greater diversity of leak K(+) conductances also in native tissues.


Ion channel heteromerization; KCNK10; KCNK2; electrophysiology; patch clamp; pharmacology; plasma membrane; potassium channel; ruthenium red; spadin

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